Lactic Acidodis

8/6/2019 Lactic Acidodis

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Lactic Acidosis

Dr. Dalia Ragab

Ass. Prof. of Critical Care Medicine

Cairo University


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Lactate Metabolism

Lactate is the end product of anaerobic glycolysis:

Glucose + 2 ATP + 2 H2PO4 2 Lactate + 2 ADP + 2 H2O

Note that this reaction produces lactate, a negatively charged

ion, notlactic acid.

The hydrogen ions needed to convert lactate to lactic acid must

be generated by the hydrolysis of ATP


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Lactate is not synonymous with lactic acid, and

hyperlactatemia is not synonymous with lactic acidosis.

Most of the lactate production occurs in:

Skeletal muscle,

Bowel,

Brain, and

Erythrocytes.

The lactate generated in these tissues can be taken up by the liver

and converted to glucose (via gluconeogenesis) or can be used asa primary oxidative fuel.


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The Lactate Shuttle

The anaerobic metabolism of one mole of glucose generates 47

kilocalories (kcal), which is only 7% of the energy yield from

complete oxidation of glucose (673 kcal).

This energy difference can be erased by the oxidation of lactate,

which generates 652 kcal per mole of glucose (326 kcal per mole of

lactate).

The use of lactate as an oxidative fuel (called the lactate

shuttle) has been described in exercise.


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The lactate shuttle could also operate in critically ill patients, there is

evidence that the hyperlactatemia in sepsis (inhibition of glucose

utilization by endotoxin).

If the effects of endotoxin predominated in one organ (e.g.,

skeletal muscle), lactate that is generated could be used as a source

of energy by other vital organs, such as the heart and central nervous

system.

In fact, both of these organs can use lactate as an energy source.

This view of lactate is very different than the traditional view of

lactate as a source of acidosis that can damage tissues.


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Each day the body has an excess production of about 1500

mmols of lactate (about 20 mmols/kg/day) which enters the

blood stream and is subsequently metabolised mostly in theliver.

This internal cycling with production by the tissues and

transport to and metabolism by the liver and kidney is known

as the Cori cycle.

All tissues can produce lactate under anaerobic conditions

but tissues with active glycolysis produce excess lactate from

glucose under normal conditions and this lactate tends to

spill over into the blood.

Lactate is produced from pyruvate in a reaction catalysed bylactate dehydrogenase:

Pyruvate + NADH + H+ Lactate + NAD+


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At rest, the tissues which normally produce excess lactate

are:

1. skin - 25% of production

2. red cells - 20%

3. brain - 20%

4. muscle - 25%

5. gut - 10%

During heavy exercise, the skeletal muscles contribute

most of the much increased circulating lactate.


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Definition:

Definitions differ concerning the blood level at which a lactic

acidosis is regarded as 'significant'. For our purposes:Hyperlactaemia: a level from 2 mmols/l to 5 mmol/l.

Severe Lactic Acidosis: when levels are greater than 5

mmol/l

Lactic acidosis can occur due to:

excessive tissue lactate productionimpaired hepatic metabolism of lactate


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Classification of Some Causes of Lactic Acidosis (Cohen & Woods, 1976)

Type A Lactic Acidosis : Clinical Evidence of Inadequate Tissue Oxygen Delivery

y Anaerobic muscular activity (eg sprinting, generalised convulsions)

y Tissue hypoperfusion (eg shock -septic, cardiogenic or hypovolaemic; hypotension; cardiac

arrest; acute heart failure; regional hypoperfusion esp mesenteric ischaemia; malaria)

y Reduced tissue oxygen delivery or utilisation (eg hypoxaemia, carbon monoxide poisoning,

severe anaemia)

Type B Lactic Acidosis: No Clinical Evidence of Inadequate Tissue Oxygen Delivery

y type B1 :Associated with underlying diseases (eg ketoacidosis, leukaemia, lymphoma,

AIDS)

y type B2:Assoc with drugs & toxins (eg phenformin, cyanide, beta-agonists, methanol,

nitroprusside infusion, ethanol intoxication in chronic alcoholics, anti-retroviral drugs)

y type B3:Assoc with inborn errors of metabolism (eg congenital forms of lactic acidosis

with various enzyme defects eg pyruvate dehydrogenase deficiency)

Note: This list does not include all causes of lactic acidosis


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Circulatory Shock

An increase in blood lactate levels in patients who are hemodynamically

unstable is taken as evidence of impaired oxygen utilization by cells (cell

dysoxia).

This condition is generally known as circulatory shock. The degree of

elevation in blood lactate levels is directly correlated with the mortalityrate in circulatory shock.

It is important to emphasize that a decrease in systemic oxygen delivery,

as occurs with anemia and hypoxemia, is not a cause of

hyperlactatemia.


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Sepsis:

Systemic sepsis is often accompanied by hyperlactatemia. Some

patients with sepsis have mild elevations of blood lactate (2 to 5 mEq/L)

with a normal lactate:pyruvate ratio and a normal blood pH. These

patients have stress hyperlactatemia, which is considered a result of

hypermetabolism without impaired cellular oxygen utilization.

Patients with septic shock can have marked elevations in blood lactate

with increased lactate:pyruvate ratios and a reduced blood pH. These

patients have a defect in cellular oxygen utilization that has been called

cytopathic hypoxia.This condition may not be associated with impaired

tissue oxygenation, but may be due to a defect in oxygen utilization in

mitochondria. One contributing factor could be endotoxin-mediated

inhibition ofpyruvate dehydrogenase, the enzyme that initiates pyruvate

oxidation in the mitochondria


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Thiamine Deficiency:

Thiamine serves as a co-factor for the pyruvate dehydrogenase enzyme

that initiates pyruvate oxidation in the mitochondria.

Therefore, it is no surprise that thiamine deficiency can be

accompanied by hyperlactatemia .

Because thiamine deficiency may be common in critically ill patients,

this diagnosis should be considered in all cases of unexplained

hyperlactatemia in the ICU.


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Drugs:

A variety of drugs can produce hyperlactatemia, including:

acetaminophen,

epinephrine,

metformin,

propofol, and

nitroprusside.

In most of these cases (except epinephrine), the lactic

acidosis indicates a defect in oxygen utilization, and carries

a poor prognosis.


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Propylene Glycol:

Propylene glycol is an alcohol used to enhance the water solubility of many

hydrophobic intravenous medications, including lorazepam, diazepam, esmolol,nitroglycerin, and phenytoin. About 5575% of propylene glycol is metabolized by

the liver and the primary metabolites are lactate and pyruvate .

Propylene glycol toxicity from solvent accumulation has been reported in 19% to

66% of ICU patients receiving high dose lorazepam or diazepam for more than 2

days .

Signs of toxicity include agitation, coma, seizures, tachycardia, hypotension, and

hyperlactatemia (which can exceed 10 mEq/L). The clinical presentation can mimic

that of systemic sepsis.

Propylene glycol toxicity is probably much more common than suspected in patients

receiving infusions of lorazepam and diazepam. This condition should be suspected

in any patient with unexplained hyperlactatemia who is on a continuous infusion ofone of these drugs.

If suspected, the drug infusion should be stopped and another sedative agent

selected.

Midazolam does not have propylene glycol as a solvent, and could be used for

short-term sedation.


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Lactic Alkalosis:

Severe alkalosis (respiratory or metabolic) can raise blood lactate

levels as a result of increased activity of pH dependent enzymes in

the glycolytic pathway .

When liver function is normal, the liver clears the extra lactate

generated during alkalosis, and lactic alkalosis becomes evident

only when the blood pH is 7.6 or higher.

However, in patients with impaired liver function, hyperlactatemia

can be seen with less severe degrees of alkalemia.


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Other Causes:

O

ther possible causes of hyperlactatemia in patients in the ICU areseizures (from increased lactate production), hepatic insufficiency

(from reduced lactate clearance), and acute asthma (possibly from

enhanced lactate production by the respiratory muscles).

Hyperlactatemia associated with hepatic insufficiency is often mild

and not accompanied by lactic acidosis.

Hyperlactatemia that accompanies generalized seizures can be

severe but is transient.

Hyperlactatemia during nitroprusside infusions is a manifestation of

cyanide intoxication and is an ominous sign.


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D-Lactic Acidosis:

The lactate produced by mammalian tissues is a levo-isomer,

whereas a dextro-isomer of lactate is produced by certain strains

of bacteria that can populate the bowel.

D-lactate generated by bacterial fermentation in the bowel can gain

access to the systemic circulation and produce a metabolic acidosis,

often combined with a metabolic encephalopathy.

Most cases of D-lactic acidosis have been reported after extensive

small bowel resection or after jejunoileal bypass for morbid obesity.


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Diagnosis:

The Anion Gap:The anion gap should be elevated in lactic acidosis, but there are

numerous reports of a normal anion gap in patients with lactic

acidosis.

As a result, the anion gap should not be used as a screening test for

lactic acidosis.

Blood Lactate:

Lactate concentrations can be measured in plasma or whole blood. If

immediate measurements are unavailable, the blood sample should beplaced on ice to retard lactate production by red blood cells in the

sample.

A lactate level above 2 mEq/L is abnormal, but in patients with sepsis,

a blood lactate level above 4 mEq/L may have more prognostic value.


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Why do clinicians have difficulty diagnosing lactic acidosis?

The main reason is that traditionally a lactate level was an uncommon

investigation and the diagnosis of lactic acidosis was by exclusion in patientswith a high anion gap metabolic acidosis and some evidence of impaired

perfusion. Other factors were a low index of clinical suspicion and a tendency to

not appreciate the significance of an elevated lactate result.

The basic investigations needed to supplement the history, examination and

electrolyte results in differentiating the causes of a high anion gap acidosis are:

blood glucose level

urinary ketones

urea & creatinine

urine output

blood lactate level

calculation of osmolar gap


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Alkali Therapy for Lactic Acidosis

Acidosis Is Not Harmful

Bicarbonate Is Not an Effective Buffer

Bicarbonate Can Be Harmful

Carbicarb

Treatment of lactic acidosis:

Is treatment of the underlying cause

The principles of management of patients with lactic acidosis are:Diagnose and correct the underlying condition (if possible)Restore adequate tissue oxygen delivery (esp restore adequateperfusion)A

void sodium bicarbonate (except possibly for treatment ofassociated severe hyperkalaemia)


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Carbicarb:

Carbicarb is a commercially available buffer solution

that is a 1:1 mixture of sodium bicarbonate and

disodium carbonate. Carbicarb has less bicarbonate

and a much lower PCO2 than the standard 7.5%

sodium bicarbonate solution. As a result, Carbicarb

does not produce the increase in PCO2 seen with

sodium bicarbonate infusions.


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Alkali Therapy for Lactic Acidosis:

The primary goal of therapy in lactic acidosis is to

correct the underlying metabolic abnormality. Alkali therapy aimed at correcting the pH is of

questionable value.

The following is a brief summary of the pertinentissues regarding alkali therapy for lactic acidosis.


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Acidosis Is Not Harmful:

The principal fear from acidosis is the risk of impaired

myocardial contractility. However, in the intact organism,

acidemia is often accompanied by an increase in cardiac

output.

This is explained by the ability of acidosis to stimulate

catecholamine release from the adrenals and to produce

vasodilation.

Therefore, impaired contractility from acidosis is less of a

concern in the intact organism.Furthermore, acidosis may have a protective role in the setting

of clinical shock. For example, extracellular acidosis has been

shown to protect energy-depleted cells from cell death.


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Bicarbonate Is Not an Effective BufferSodium bicarbonate is the standard buffer used for lactic

acidosis, but has limited success in raising the serum pH. This

can be explained by the titration curve for the carbonic acid-bicarbonate buffer system.

The HCO3 buffer pool is generated by the dissociation of

carbonic acid (H 2CO3):

The dissociation constant (pK) for carbonic acid (i.e., the pH atwhich the acid is 50% dissociated) is 6.1, as indicated on the

titration curve. Buffers are most effective within 1 pH unit on

either side of the pK, so the effective range of the bicarbonate

buffer system should be an extracellular pH between 5.1 and

7.1 pH units (indicated by the shaded area on the titrationcurve). Therefore, bicarbonate is not expected to be an

effective buffer in the usual pH range of extracellular fluid.

Bicarbonate is not really a buffer (at least in the pH range we

live in); rather, it is a transport form for carbon dioxide in blood


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Bicarbonate Can Be Harmful:

A number of undesirable effects are associated with sodium

bicarbonate therapy:

Ability to generate CO2 and actually lower the intracellularpH and cerebrospinal fluid pH.

In fact, considering that the PCO2 is 200 mm Hg in

standard bicarbonate solutions,bicarbonate is really a

CO2 burden (an acid load!) that must be removed by the

lungs


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Summary:

Sodium bicarbonate has no role in the management of lactic

acidosis. However, in the setting of severe acidosis (pH < 7.1)

where the patient is deteriorating rapidly, a trial infusion of

bicarbonate can be attempted by administering one-half of the

estimated bicarbonate deficit.

(where 15 mEq/L is the end-point for the plasma HCO3).

If cardiovascular improvement occurs, bicarbonate therapy

can be continued to maintain the plasma HCO3 at 15 mEq/L.

If no improvement or further deterioration occurs, further

bicarbonate administration is not warranted.

Acid-Base Physiology

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Lactic Acidodis